Cytokines, Inflammation and Pain

Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. They are key players in the regulation of the immune response, particularly during infections, inflammatory joint, kidney, vessel and bowel diseases, or neurological and endocrinological autoimmune diseases. 

Cytokines include:

• Lymphokine
• Cytokines made by lymphocytes
• Monokine
• Cytokines made by monocytes and macrophages
• Chemokine
• Cytokines with chemotactic activities
• Interleukin (ILs)
• Cytokines made by one leukocyte and acting on other leukocytes
• Interferons (IFNs)
• Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses.
• Tumour necrosis factors

but not hormones or growth factors. Unlike hormones, cytokines are not stored in glands as preformed molecules, but are rapidly synthesized and secreted by different cells mostly after stimulation.

Figure 1. Cytokines act in networks or cascades. They are a category of signaling molecules that mediate and regulate immunity, inflammation, hematopoiesis, and many other cellular processes.

Cytokine Network

Cytokines act in networks or cascades.  Several different cell types coordinate their efforts as part of the immune system. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted cytokines.

A given cytokine may be produced by more than one type of cell.  They act through cell surface receptors.  

Cytokines are produced by a broad range of cells, but the predominant producers are helper T cells (Th) and macrophages, including immune cells like:

• Macrophages
• Macrophages are phagocytic cells that are produced during an injury or infection.
• Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types.
• B Cells
• Unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines.
• However, there are a large number of cytokines that act on B cells that play significant roles in the development, survival, differentiation and proliferation of B cells.
• T Cells
• Killer T cells can use cytokines to recruit other types of cells when mounting an immune response.
• Helper T cells also use cytokine signaling to influence regulatory B cells directly, and other cell populations indirectly.
• Mast cell
• Endothelial cells
• Fibroblasts, and
• Various stromal cells

The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well (see Figure 1).

Summary of cytokines and their functions

• Th1 cytokines
• Cytokines produced by Th1 T-helper cells 
• Include IL-2, IFN-γ, IL-12  & TNF-β
• IFN-γ is the defining cytokines for Th1 cells, which enhances inflammatory functions that support viral clearance
• Innate mediators of Th1-driven pathology are powerful across diseases.^[14]
• Scientists found that liver-resident Kupffer cells induced neutrophil-mediated liver toxicity by producing IL-12 and responding to IFN-γ. Inhibition of the neutrophil response limited liver toxicity.
• Th2 cytokines 
• Cytokines produced by Th2 T-helper cells
• Include IL-4 , IL-5, IL-6, IL-10, and IL-13
• IL-4 is the defining cytokines for Th2 cells
• Th17 cytokines
• include IL-17, TGF-beta, IL-6
• IL-17 is the defining cytokines for Th17 cells
• Th17 cells play a role in host defense against extracellular pathogens, particularly at the mucosal and epithelial barriers, but aberrant activation has been linked to the pathogenesis of various autoimmune diseases.^[13]

Cytokine	Family	Main sources	Function
IL-1β	IL-1	Macrophages, monocytes	Pro-inflammation, proliferation, apoptosis, differentiation
IL-4	IL-4	Th-cells	Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation
IL-6	IL-6	Macrophages, T-cells, adipocyte	Pro-inflammation, differentiation, cytokine production
IL-8	CXC	Macrophages, epithelial cells, endothelial cells	Pro-inflammation, chemotaxis, angiogenesis
IL-10	IL-10	Monocytes, T-cells, B-cells	Anti-inflammation, inhibition of the pro-inflammatory cytokines
IL-11	IL-6	Fibroblasts, neurons, epithelial cells	Anti-inflammation, differentiation, induces acute phase protein
IL-12	IL-12	Dendritic cells, macrophages, neutrophils	Pro-inflammation, cell differentiation, activates NK cell
IL-13	IL-13/ IL-4	Th2, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils, nuocytes	Anti-inflammation; Central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation; Also, a mediator of allergic inflammation and different diseases including asthma.
TNF-α	TNF	Macrophages, NK cells, CD4+lymphocytes, adipocyte	Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection, play a damaging role in many inflammatory diseases
IFN-γ	INF	T-cells, NK cells, NKT cells	Pro-inflammation, innate, adaptive immunity anti-viral
GM-CSF	IL-4	T-cells, macrophages, fibroblasts	Pro-inflammation, macrophage activation, increase neutrophil and monocyte function
TGF-β	TGF	Macrophages, T cells	Anti-inflammation, inhibition of pro-inflammatory cytokine production

 

Inflammation and Pain

Inflammation is part of the body’s defense mechanism and plays a role in the healing process. 

The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function. 

While the sensation is a very individualized experience, inflammation typically causes pain because the swelling and buildup of tissue starts pressing against nerve endings. This pressure sends pain signals to the brain, causing discomfort.

There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and are related to the development of contralateral hyperalgesia/allodynia.

Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.  Their functions also include:

• Modulate the balance between humoral and cell-based immune responses
• Regulate the maturation, growth, and responsiveness of particular cell populations
• Enhance or inhibit the action of other cytokines in complex ways

Pro-Inflammatory vs Anti-Inflammatory

There are both pro-inflammatory cytokines and anti-inflammatory cytokines:

• Proinflammatory cytokines 
• Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defense against pathogens mediating the innate immune response. 
• Some inflammatory cytokines have additional roles such as acting as growth factors.
• They are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. 
• There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.
• Anti-Inflammatory cytokines
• Major anti-inflammatory cytokines include IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. 
• IL-10 is considered a prototypical anti-inflammatory cytokine, and is the most widely studied of the anti-inflammatory interleukins.
• Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.^[4]
• Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.^[5]
• As a result, TNFα levels rise and result in inflammation.^[6]
• TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.

LIF, IFN-α, IL-6, and TGF-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances.

References

1. Cytokines, Inflammation and Pain
2. B cells responses and cytokine production are regulated by their immune microenvironment
3. Expression and Function of Anti-Inflammatory Interleukins: The Other Side of the Vascular Response to Injury
4. Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisäkk P, Fredrikson S, Link H (May 1999). "Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment". Scandinavian Journal of Immunology. 49 (5): 554–61. 
5. Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez-Iglesias M, Takata M (April 2008). "Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism". European Journal of Immunology. 38 (4): 1106–17.
6. Nakahara J, Maeda M, Aiso S, Suzuki N (February 2012). "Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy". Clinical Reviews in Allergy & Immunology. 42 (1): 26–34. 
7. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome
8. Essential involvement of interleukin-8 (IL-8) in acute inflammation
• IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.
• Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. 
9. The role of interleukin-8 in inflammation and mechanisms of regulation
10. Coronavirus Deranges the Immune System in Complex and Deadly Ways
11. The role of IL-13 and its receptor in allergy and inflammatory responses
12. Annunziato F, Cosmi L, Liotta F, et al. Human Th1 dichotomy: origin, phenotype and biologic activities. Immunology 2014.
• IFN-γ is the most important cytokine, that is associated with the Th1 immune response.
13. Awasthi A, Kuchroo VK (2009) Th17 cells: From precursors to players in inflammation and infection. Int Immunol 21:489–498.
14. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy